Objective Identification of the neural mechanisms underlying medication overuse headache resulting from triptans. Methods Triptans were administered systemically to rats by repeated intermittent injections or by continuous infusion over 6 days. Periorbital and hind paw sensory thresholds were measured to detect cutaneous allodynia. Immunofluorescent histochemistry was employed to detect changes in peptidic neurotransmitter expression in identified dural afferents. Enzyme-linked immunoabsorbent assay was used to measure calcitonin gene-related peptide (CGRP) levels in blood. Results Sustained or repeated administration of triptans to rats elicited time-dependent and reversible cutaneous tactile allodynia that was maintained throughout and transiently after drug delivery. Triptan administration increased labeling for CGRP in identified trigeminal dural afferents that persisted long after discontinuation of triptan exposure. Two weeks after triptan exposure, when sensory thresholds returned to baseline levels, rats showed enhanced cutaneous allodynia and increased CGRP in the blood following challenge with a nitric oxide donor. Triptan treatment thus induces a state of latent sensitization characterized by persistent pronociceptive neural adaptations in dural afferents and enhanced responses to an established trigger of migraine headache in humans. Interpretation Triptans represent the treatment of choice for moderate and severe migraine headaches. However, triptan overuse can lead to an increased frequency of migraine headache. Overuse of these medications could induce neural adaptations that result in a state of latent sensitization, which might increase sensitivity to migraine triggers. The latent sensitization could provide a mechanistic basis for the transformation of migraine to medication overuse headache.

OBJECTIVE-To develop and validate a model of cutaneous allodynia triggered by dural inflammation for pain associated with headaches. To explore neural mechanisms underlying cephalic and extracephalic allodynia. METHODS-Inflammatory mediators (IM)were applied to the dura of unanesthetized rats via previously implanted cannulas and sensory thresholds of the face and hindpaws were characterized.RESULTS-IM elicited robust facial and hindpaw allodynia which peaked within 3 hr. These effects were reminiscent of cutaneous allodynia seen in patients with migraine or other primary headache conditions, and were reversed by agents used clinically in treatment of migraine, including sumatriptan, naproxen, and a CGRP-antagonist. Consistent with clinical observations the allodynia was unaffected by an NK-1 antagonist. Having established facial and hindpaw allodynia as a useful animal surrogate of headache-associated allodynia, we next showed that blocking pain-facilitating processes in the rostral ventromedial medulla (RVM) interfered with its expression. Bupivacaine, destruction of putative pain-facilitating neurons or block of cholecystokinin receptors prevented or significantly attenuated IM-induced allodynia. Electrophysiological studies confirmed activation of pain-facilitating RVM ON cells and transient suppression of RVM OFF cells following IM.INTERPRETATION-Facial and hindpaw allodynia associated with dural stimulation is a useful surrogate of pain associated with primary headache including migraine and may be exploited mechanistically for development of novel therapeutic strategies for headache pain. The data also demonstrate the requirement for activation of descending facilitation from the RVM for the expression of cranial and extracranial cutaneous allodynia and are consistent with a brainstem generator of allodynia associated with headache disorders.

A puzzling observation is why peripheral nerve injury results in chronic pain in some, but not all, patients. We explored potential mechanisms that may prevent the expression of chronic pain. Sprague-Dawley (SD) or Holtzman (HZ) rats showed no differences in baseline sensory thresholds or responses to inflammatory stimuli. However, spinal nerve ligation (SNL)-induced tactile allodynia occurred in approximately 85% of SD and 50% of HZ rats, respectively. No apparent differences were observed in a survey of DRG or spinal “neuropathic markers” following SNL regardless of allodynic phenotype. SNL-induced allodynia was reversed by administration of lidocaine within the rostral ventromedial medulla (RVM), a site that integrates descending pain modulation via pain inhibitory (i.e., OFF) and excitatory (i.e., ON) cells. However, in SD or HZ rats with SNL but without allodynia, RVM lidocaine precipitated allodynia. Additionally, RVM lidocaine produced conditioned place preference in allodynic SD or HZ rats but conditioned place aversion in non-allodynic HZ rats. Similarly, RVM U69,593 (kappa opioid agonist) or blockade of spinal α2 adrenergic receptors precipitated allodynia in previously non-allodynic HZ rats with SNL. All rats showed an equivalent first phase formalin responses. However, HZ rats had reduced second phase formalin behaviors along with fewer RVM OFF cell pauses and RVM ON cell bursts. Thus, expression of nerve-injury induced pain may ultimately depend on descending modulation. Engagement of descending inhibition protects in the transition from acute to chronic pain. These unexpected findings might provide a mechanistic explanation for medications that engage descending inhibition or mimic its consequences.

BackgroundDespite advances in our understanding of basic mechanisms driving post-surgical pain, treating incision-induced pain remains a major clinical challenge. Moreover, surgery has been implicated as a major cause of chronic pain conditions. Hence, more efficacious treatments are needed to inhibit incision-induced pain and prevent the transition to chronic pain following surgery. We reasoned that activators of AMP-activated protein kinase (AMPK) may represent a novel treatment avenue for the local treatment of incision-induced pain because AMPK activators inhibit ERK and mTOR signaling, two important pathways involved in the sensitization of peripheral nociceptors.ResultsTo test this hypothesis we used a potent and efficacious activator of AMPK, resveratrol. Our results demonstrate that resveratrol profoundly inhibits ERK and mTOR signaling in sensory neurons in a time- and concentration-dependent fashion and that these effects are mediated by AMPK activation and independent of sirtuin activity. Interleukin-6 (IL-6) is thought to play an important role in incision-induced pain and resveratrol potently inhibited IL-6-mediated signaling to ERK in sensory neurons and blocked IL-6-mediated allodynia in vivo through a local mechanism of action. Using a model of incision-induced allodynia in mice, we further demonstrate that local injection of resveratrol around the surgical wound strongly attenuates incision-induced allodynia. Intraplantar IL-6 injection and plantar incision induces persistent nociceptive sensitization to PGE2 injection into the affected paw after the resolution of allodynia to the initial stimulus. We further show that resveratrol treatment at the time of IL-6 injection or plantar incision completely blocks the development of persistent nociceptive sensitization consistent with the blockade of a transition to a chronic pain state by resveratrol treatment.ConclusionsThese results highlight the importance of signaling to translation control in peripheral sensitization of nociceptors and provide further evidence for activation of AMPK as a novel treatment avenue for acute and chronic pain states.

Migraine headache is one of the most common neurological disorders. The pathological conditions that directly initiate afferent pain signaling are poorly understood. In trigeminal neurons retrogradely labeled from the cranial meninges, we have recorded pH-evoked currents using whole-cell patch-clamp electrophysiology. Approximately 80% of dural afferent neurons responded to a pH 6.0 application with a rapidly activating and rapidly desensitizing ASIC-like current that often exceeded 20 nA in amplitude. Inward currents were observed in response to a wide range of pH values and 30% of the neurons exhibited inward currents at pH 7.1. These currents led to action potentials in 53%, 30% and 7% of the dural afferents at pH 6.8, 6.9 and 7.0, respectively. Small decreases in extracellular pH were also able to generate sustained window currents and sustained membrane depolarizations. Amiloride, a non specific blocker of ASIC channels, inhibited the peak currents evoked upon application of decreased pH while no inhibition was observed upon application of TRPV1 antagonists. The desensitization time constants of pH 6.0-evoked currents in the majority of dural afferents was less than 500 ms which is consistent with that reported for ASIC3 homomeric or heteromeric channels. Finally, application of pH 5.0 synthetic-interstitial fluid to the dura produced significant decreases in facial and hind-paw withdrawal threshold, an effect blocked by amiloride but not TRPV1 antagonists, suggesting that ASIC activation produces migraine-related behavior in vivo. These data provide a cellular mechanism by which decreased pH in the meninges following ischemic or inflammatory events directly excites afferent pain-sensing neurons potentially contributing to migraine headache.